2-(N-cyanoimino)thiazolidin-4-one derivatives

ABSTRACT

This invention provides novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I or a pharmaceutically acceptable salt or solvate thereof:                    
     wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C 1 -C 4  alkyl group, a haloalkyl group, a halogen atom or —OR 5 , 
     R 1  represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C 1 -C 4  alkylene or alkenylene group optionally substituted by a phenyl group, R 6 —X, X—R 6 , X—R 6 —X, R 6 —X—R 6 , —C(═O)—NR 7 — or —NR 7 —C(═O)—, 
     R 2  and R 3  are the same or different and each represents a hydrogen atom, a C 1 -C 4  alkyl group, —OR 8  or a halogen atom, 
     R 4  represents a hydrogen atom or a C 1 -C 4  alkyl group, 
     R 5  represents a hydrogen atom or a C 1 -C 4  alkyl group, 
     R 6  represents a straight or branched C 1 -C 4  alkylene or alkenylene group, 
     R 7  represents a hydrogen atom or a C 1 -C 4  alkyl group, 
     R 8  represents a hydrogen atom, a C 1 -C 4  alkyl group or an aralkyl group, 
     X represents an oxygen atom or a sulfur atom. 
     They have excellent activities of lowering triglyceride and cholesterol levels, and are useful for preventing from and/or treating hyperlipidemia and related complications.

This application is a 371 application of PCT/JP99/06352, filed Nov. 12, 1999.

TECHINICAL FIELD

The invention relates to novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or pharmaceutically acceptable salts or solvates thereof, which have excellent activities in a lowering blood triglyceride level and a cholesterol level, and are useful for prevention from and/or treatment of hyperlipidemia and related complications.

BACKGROUND ART

Many epidemiological studies have shown that hypercholesterolemia is a risk factor for coronary heart disease (CHD). Recently, hypertriglycemia is confirmed to be an independent risk factor for CHD. (J Jpn Atheroscler Soc, 25 (1-2), 1-34 (1997)—Guideline for Diagnosis and Treatment of Hyperlipidernias in Adults).

For the therapy of hypertriglycemia, dextran sulfate sodium, nicotinic acid derivatives, fibric acid derivatives (fibrates) have been used as the first choice. In particular bezafibrate is known to have more potent cholesterol lowering property as well as triglyceride lowering property than the earlier fibrates. And for hypercholesterolemia, HMG-CoA reductase inhibitors (e.g. pravastatin, simvastatin, etc., known as statins) are generally provided for clinical use.

When blood cholesterol level alone is elevated, HMG-CoA reductase inhibitors are employed. However, when both levels of blood cholesterol and triglyceride are elevated or the effect of hypolipidemic agent is not sufficient, some lipid lowering drugs are combined.

Thus, an aim of the present invention is to provide a novel class of potent hypolipidemic agents, which reduce more effectively a blood triglyceride level or both levels of blood triglycerides and cholesterol.

Some antidiabetic agents that are partially analogous to the compounds of the present invention have been found and developed, for example, troglitazone and pioglitazone. However, they are thiazolidin-2,4-dione derivatives, and according to the conference abstract of the 28th Meeting of the Japan Atherosclerosis Society, Osaka,. June, 1996, No.024, pioglitazone did not change total cholesterol and triglyceride levels in hyperlipidemic rabbits. Therefore, from a view of chemical and biological properties, the compounds of the present invention are considered to be different from those antidiabetic compounds.

DISCLOSURE OF INVENTION

This invention provides prophylactic or therapeutic agents for hyperlipidemia and related complications comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I or a pharmaceutically acceptable salt or solvate thereof as active ingredients:

wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C₁-C₄ alkyl group, a haloalkyl group, a halogen atom or —OR⁵;

R¹ represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C₁-C₄ alkylene or alkenylene group optionally substituted by a phenyl group, R⁶—X, X—R⁶, X—R⁶—X, R⁶—X—R⁶, —C(═O)—NR⁷— or —NR⁷—C(═O)—;

R² and R³ are the same or different and each represents a hydrogen atom, a C₁-C₄ alkyl group, —OR⁸ or a halogen atom,

R⁴ represents a hydrogen atom or a C₁-C₄ alkyl group;

R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group;

R⁶ represents a straight or branched C₁-C₄ alkylene or alkenylene group;

R⁷ represents a hydrogen atom or a C₁-C₄ alkyl group;

R⁸ represents a hydrogen atom, a C₁-C₄ alkyl group or an aralkyl group;

X represents an oxygen atom or a sulfur atom.

The present inventors have carried out various investigations to solve the above problem and found that the novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I have excellent blood triglyceride lowering and cholesterol lowering activities. Thus the present invention was successfully established.

BEST MODE FOR CARRYING OUT THE INVENTION

“Salts” refers to low toxic salts derived from sodium, potassium, ammonia or organic amines, for instance.

“C₁-C₄ alkyl group” refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, for instance.

“C₁-C₄ alkoxy group” refers to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert-butoxy, for instance.

“halogen atom” refers to generally fluorine atom, chlorine atom, bromine atom or iodine atom. More preferably it is fluorine atom or chlorine atom.

“ring A” refers to a benzene ring, a benzodioxole ring, a benzofuran ring, a benzothiazole, a fluorene ring, an indan ring, an indoline ring or a pyridine ring, connecting with R¹ at any position, for instance.

Particularly preferred compounds represented by formula I are as follows:

2-(N-Cyanoimino)-5-[(E)-4-stylylbenzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[(E)-4-(a-methylstylyl)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(benzyloxymethyl)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[(E)-4-(b-methylstylyl)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(3-phenylpropoxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(4-chlorophenoxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-(4-phenylthiobenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[(E)-4-(2-fluorostylyl)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(2,5-dimethylphenoxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-(4-phenethyloxybenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(2-phenylpropoxy)benzylidene]thiazolidin-4-one

2-(N-Cyanoimino)-5-(3-phenethyloxybenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-(4-benzyloxybenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(5-chlorobenzofuran-2-yl)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[(E)-4-(4-methoxystylyl)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-(3-phenoxybenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(1,3-benzodioxol-5-ylmethoxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(4-methylbenzyloxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(4-chlorobenzyloxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[3-methoxy-(E)-4-stylylbenzylidene]thiazolidin-4-one;,

2-(N-Cyanoimino)-5-(2-phenethyloxybenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-(4-phenoxybenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[3-(benzyloxy)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-(benzylthio)benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-(4-phenethylbenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[4-[2-(4-chlorophenyl)ethoxy]benzylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-[1-[(E)-4-(4-methoxystylyl)phenyl]ethylidene]thiazolidin-4-one;

2-(N-Cyanoimino)-5-(4-benzyloxy-2,5-dimethylbenzylidene)thiazolidin-4-one;

2-(N-Cyanoimino)-5-[(E)-3-stylylbenzylidene]thiazolidin-4-one;

The compounds of the present invention are novel compounds not described in any literature and can be prepared by the following methods as the example.

A 2-(N-cyanoimino)thiazolidin-4-one represented by formula II or the salts thereof are reacted with an aldehyde or ketone represented by formula III

wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C₁-C₄ alkyl group, a haloalkyl group, a halogen atom or —OR⁵;

R¹ represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C₁-C₄ alkylene or alkenylene group optionally substituted by a phenyl group, R⁶—X, X—R⁶, X—R⁶—X, R⁶—X—R⁶, —C(═O)—NR⁷— or —NR⁷—C(═O)—;

R² and R³ are the same or different and each represents a hydrogen atom, a C₁-C₄ alkyl group, —OR⁸ or a halogen atom;

R⁴ represents a hydrogen atom or a C₁-C₄ alkyl group;

R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group;

R⁶ represents a straight or branched C₁-C₄ alkylene or alkenylene group;

R⁷ represents a hydrogen atom or a C₁-C₄ alkyl group;

R⁸ represents a hydrogen atom, a C₁-C₄ alkyl group or an aralkyl group;

X represents an oxygen atom or a sulfur atom.

The reaction can be carried out in a suitable solvent such as ethanol, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, toluene, and xylene, alternatively without employing a solvent, in the presence of ammonium acetate at a temperature ranged from ambient temperature to 200° C., preferably from 70° C. to 150° C., for a period of time between 10 minutes to 10 hours, usually 20 minutes to 5 hours.

There are geometric isomers for the present compounds, however, in solution, reversible isomerization of C5-double bond of thiazolidine occurs very easily by the action of light or heat.

The compounds of the present invention have excellent activities in lowering blood triglyceride and cholesterol levels and are pharmaceutically useful as therapeutic agents for prevention and/or treatment of hyperlipidemia and related complications.

The compounds of the present invention and pharmaceutically acceptable salts thereof can be orally or parenterally administered either alone or preferably in the form of appropriate pharmaceutical compositions such as tablets, powders, granules, capsules, syrups, or injections comprised of pharmaceutically acceptable carriers, diluents, solubilizers, or other pharmaceutical additives.

The dosage will depend on the condition, age, body weight, and other factors of each patient or efficacy of an active ingredient. Generally, when the compound of the present invention is orally administered, the daily dose of the present invention preferably ranges from 10 to 400 mg for adult, and is administered once or in several divided doses a day.

The invention is illustrated by the following examples.

EXAMPLE 1

2-(N-Cyanoimino)-5-[(E)-4-stylylbenzylidene]thiazolidin-4-one

A mixture of 4.48 g (0.025 mol) of 2-(N-cyanoimino)thiazolidin-4-one potassium salt, 5.47 g (0.026 mol) of trans-4-stilbencarboxaldehyde and 2.02 g (0.026 mol) of ammonium acetate in 100 mL of ethanol was heated for 2 hours under reflux. After cooling, ether was added to the reaction mixture and the precipitated potassium salt of the title compound was collected by filtration. To the rapidly stirring suspension of the salt in 50 mL of acetone, 5 mL of conc. hydrogen chloride was added dropwise and then 250 mL of water was added. The precipitate was collected and dried under reduced pressure to yield the title compound.

The structural formula, yield, and the physical property of the compound are shown in Table 1.

EXAMPLE 2 TO EXAMPLE 61

In substantially the same manner as in Example 1, the compounds shown in Table 1 were obtained.

Their structural formulas, yields, and physical properties are shown in Table 1.

Abbreviations used in Table 1 are defined as follows:

Ex. Example mp melting point recryst solv recrystallization solvent El-MS electron impact ionization mass spectroscopy IR infrared spectroscopy EA elemental analysis ¹H NMR proton nuclear magnetic resonance spectra s singlet d doublet dd doublet of doublets t triplet m multiplet br broad J coupling constant *1: After heating for 10 minutes at 130° C. without solvent, the soluble part of reaction mixture in chloroform is chromatographed on a silica gel column. *2: n-Butanol was used as solvent. *3: E = ethanol, DMF = N,N-dimethylformamide, I = isopropanol, A = acetone, M = methanol, EA = ethyl acetate, H = hexane *4: Solvent; 10% Pyridine-d5/DMSO-d6

TABLE 1 2-(N-Cyanoimino)thiazolidin-4-ones

Ex. No. Description Yield (%) R R′

EI-MS (m/z)  1 yellow crystals 88

H 265 (dec) (E-DMF) 331(M⁺), 236, 202, 179  2 orange-yellow crystals 84

H 226-227.5 (E-DMF) 345(M⁺), 258, 243, 162  3 pale yellow crystals 90

H 170.5-171.5 (E-DMF) 349(M⁺), 320, 258, 243, 230, 162, 147, 135, 115, 103, 91, 79, 77  4 yellow needles 66

H 236.5-237.5 (E-DMF) 345(M⁺), 320, 249, 233, 205  5 yellow crystals 78

H 212.5-213 (dec) (E-DMF) 363(M⁺), 272, 268, 245, 176, 150, 121, 91, 65  6 orange-yellow needles 69

H 225-226.5 (dec) (E-DMF) 355(M⁺), 262, 260, 149  7 orange crystals 76

H 204.5-205.5 (dec) (E-DMF) 337(M⁺), 242, 200, 197, 165  8 yellow crystals 91

H 271-272 (E-DMF) 349(M⁺), 254  9 orange-yellow plates 62

H 196-197.5 (E) 349(M⁺), 254, 121, 149, 134, 221, 105, 79 10 pale yellow crystals 78

H 193-194 (dec) (I-DMF) 349(M⁺), 150, 105, 79 11 pale yellow crystals 66

H 190-191 (E-DMF) 363(M⁺), 244, 210, 149 12 pale yellow crystals 80

H 172-173 (dec) (E-DMF) 349(M⁺), 150, 105 13 yellow brown crystals 60

H 230-231 (dec) (E-DMF) 335(M⁺), 149, 121, 91 14 yellow needles 56

H 265 (dec) (E-DMF) 379(M⁺), 286, 284 15 yellow crystals quant.

H 161-162 (E-DMF) 361(M⁺), 266, 251, 234, 221, 189, 179, 165, 133, 105, 89, 77 16 Light-brown crystals 93

H 202.5-203.5 (E-DMF) 321(M⁺), 226, 197, 165 17 yellow crystals 95

H 217-218 (dec) (E-DMF) 379(M⁺), 245, 150, 135, 105, 77 18 light-orange crystals 84

H 248.5-249.5 (dec) (E-DMF) 349(M⁺), 150, 105 19 orange crystals 54

H 220-221 (dec) (E-DMF) 369(M⁺), 149, 127, 125, 105 20 red crystals 89

H 250.5 (dec) (E-DMF) 361(M⁺), 262, 234, 223, 206 21 yellow crystals 52

H 204-205.5 (dec) (E-DMF) 349(M⁺), 178, 149, 105, 77 22 pale yellow crystals 84

H 218-219 (dec) (E-DMF) 321(M⁺), 226, 197, 149, 121, 77 23 orange-yellow crystals 84

H 195-195.5 (E-DMF) 379(M⁺), 274, 180, 105, 79 24 pale yellow crystals 59

H 275 (dec) (E-DMF) 348(M⁺), 256, 161, 133, 91 25 yellow crystals 79

H 295-296 (dec) (DMF) 331[(M − 1)⁺], 236, 204, 158, 113, 79, 51 26 yellow crystals 65

H 194-195 (E) 409(M⁺), 305, 210, 105, 79 27 orange plates 79

H 202.5-203.5 (dec) (E) 362(M⁺), 105, 77 28 light brown crystals 95

H 270-271 (E-DMF) 433[(M + 2)⁺], 431(M⁺),189, 187, 149, 107 29 orange crystals 65

H >300 (E-DMF) 372(M⁺), 277 30 pale yellow crystals 68

H >300 (DMF) 371(M⁺), 276, 247, 213, 139, 114, 89 31 yellow crystals 79

H >300 (DMF) 388(M⁺), 294, 292, 260, 249, 236, 163, 149, 77 32 pale yellow crystals 70

H 144-145.5 (EA-H) 363(M⁺), 244, 210, 149 33 yellow crystals 94

H 238.5-240 (E-DMF) 335(M⁺), 250, 240, 173, 147 34 yellow crystals 93

H 253.5-255 (E-DMF) 305(M⁺), 210 35 orange crystals 82

H 240 (dec) (E-A) 373(M⁺), 358, 278, 263, 230, 202, 129, 91, 68 36 pale yellow crystals 85

H 219.5-220.5 (dec) (E-DMF) 361(M⁺), 150, 117, 91 37 yellow crystals 37

H 161.5-162.5 (E) 469(M⁺), 364, 267, 105, 77 38 orange-yellow crystals 73

H 189.5-190.5 (dec) (M) 365(M⁺), 166, 105, 79 39 orange-yellow crystals 57

H 297 (dec) (E-DMF) 348(M⁺), 197, 148, 105 40 orange crystals 55

H 257-259 (dec) (E-DMF) 405(M⁺), 310, 253, 165 41 yellow crystals 80

H 225-226.5 (dec) (E-DMF) 365(M⁺), 270, 245, 176, 150, 121, 93, 77 42 orange crystals 76

H 273-275 (dec) (E-DMF) 361(M⁺), 189, 177, 165, 147 43 yellow crystals 76

H 206-207 (dec) (E) 365(M⁺), 166, 105, 79 44 brown crystals 49

H 198-200 (E-DMF) 359(M⁺), 344, 330, 283, 264, 249, 216, 188, 147, 129, 116, 114, 91 45 yellow crystals 85

H 242-243 (E-DMF) 305(M⁺), 304, 210, 165 46 reddish-brown crystals 55

H 183.5-185 (E-DMF) 379(M⁺), 289, 273, 244, 178, 147, 91 47 yellow crystals 62

H 238-239 (E-DMF) 407(M⁺), 312, 235, 203 48 pale yellow crystals 71

H 235-236 (dec) (E-DMF) 418(M⁺), 174, 130, 78 49 pale yellow crystals 70

H 200-201.5 (E-DMF) 408(M⁺), 375, 280, 242, 147, 91 50 yellow crystals 79

H >300 (DMF) 365(M⁺), 272, 270, 234, 202, 178 51 yellow amorphous 18^(*1)

Me 69-71 363(M⁺), 164 52 yellow crystals 91

H 275-280 (dec) (E-DMF) 399(M⁺), 304, 259, 227 53 pale yellow crystals 94

H 201-202.5 (E-DMF) 335(M⁺), 245, 177, 149, 121 54 yellow crystals 73

H 282-283 (E-DMF) 351(M⁺), 260, 165, 121, 91, 65 55 yellow crystals 86

H >300 (E-DMF) 345(M⁺), 251, 178 56 orange crystals 69

H 206.5-208.5 (E-DMF) 383(M⁺), 244, 149, 139 57 yellow crystals 79

H 190-191 (E) 369(M⁺), 185, 183, 91 58 pale yellow crystals 64

H 212-214 (E-DMF) 333(M⁺), 242, 147, 91 59 yellow crystals 45

H 247-248 (E-DMF) 331(M⁺), 236, 203, 147, 103 60 orange-yellow crystals 80

H 227-228 (dec) (E-A) 363(M⁺), 177, 91 61 yellow-brown crystals 83^(*2)

Me 203-204 (E-DMF) 375(M⁺), 280, 266, 250, 232, 221, 210, 166 Ex. No. IR (KBr, cm⁻¹) ¹H-NMR(DMSO-d6, δ:ppm)

 1 3015, 2920, 2740, 2185, 1725, 1580, 5.80-7.00(1H, br), 7.20-8.10(11H, m), C₁₉H₁₃N₃OS H 3.95, C 68.86, N 12.68 1505, 1490, 1340, 1290, 1170, 580, 7.86(1H, s) (331.399) H 4.15, C 68.94, N 12.40 540, 500  2 3150, 3080, 2925, 2210, 1724, 1580, 2.27(3H, br), 3.50-4.40(1H, br), C₂₀H₁₅N₃OS H 4.38, C 69.54, N 12.16 1360, 1348, 1180, 742, 700, 588, 525 7.08(1H, br), 7.20-7.55(5H, m), 7.60- (345.426) H 4.59, C 69.51, N 11.99 7.80(4H, m), 7.88(1H, s)  3 3200, 3110, 2200, 1740, 1600, 1350, 3.86(1H, br), 4.57(2H, s), C₁₉H₁₅N₃O₂S H 4.33, C 65.31, N 12.03 1307, 1250, 1200, 1190, 1146, 830, 4.62(2H, s), 7.37(5H, s), (349.414) H 4.64, C 65.54, N 11.70 755, 562, 540 7.60(4H, s), 7.87(1H, s)  4 2950, 2200, 1717, 1598, 1360, 1293, 2.28(3H, s), 6.05(1H, br), 6.81(1H, s), C₂₀H₁₅N₃OS H 4.38, C 69.54, N 12.16 1248, 1202, 1181, 763, 721, 700, 7.20-7.80(9H, m), 7.84(1H, s) (345.426) H 4.65, C 69.62, N 11.76 582, 542, 520  5 3110, 3050, 2925, 2780, 2190, 1690, 1.50-2.37(2H, m), 2.37-2.91(2H, m), C₂₀H₁₇N₃O₂S H 4.71, C 66.10, N 11.56 1585, 1555, 1500, 1490, 1350, 1260, 4.01(2H, t, J=6Hz), (363.441) H 4.85, C 66.05, N 11.53 1245, 1205, 1170, 1110, 820, 720, 7.05(2H, d, J=8.5Hz), 7.22(5H, s), 535 7.54(2H, d, J=8.5Hz), 7.76(1H, s)  6 3160, 3075, 2945, 2770, 2200, 1720, 6.40-8.00(1H, br), 7.13 C₁₇H₁₀ClN₃O₂S H 2.83, C 57.39, N 11.81 1590, 1580, 1500, 1480, 1355, 1290, (4H, dd, J=8.5Hz, 9Hz), (355.805) H 3.13, C 57.44, N 11.54 1245, 1205, 1190, 1170, 1090, 1010, 7.49(2H, d, J=9Hz), 7.67 830, 545, 490 (2H, d, J=8.5Hz), 7.84(1H, s)  7 3125, 3040, 2930, 2750, 2200, 1730, 4.30-5.40(1H, br), 7.21(2H, d, J=9Hz), C₁₇H₁₁N₃OS₂ H 3.29, C 60.51, N 12.45 1700, 1615, 1600, 1580, 1545, 1490, 7.40(5H, s), 7.50(2H, d, J=9Hz), (337.427) H 3.57, C 60.27, N 12.38 1470, 1405, 1355, 1320, 1300, 1185, 7.71(1H, s) 1080, 755, 715, 700  8 3050, 2960, 2800, 2200, 1700, 1580 3.93(1H, br), 7.20-7.84(10H, m), C₁₉H₁₂FN₃OS H 3.46, C 65.32, N 12.03 1357, 1296, 1211, 1177, 754, 550 7.87(1H, s) (349.388) H 3.73, C 65.53, N 11.78  9 3050, 2950, 2770, 2190, 1735, 1705, 2.09, 2.27(each 3H, s), 6.30-8.50(1H, C₁₉H₁₅N₃O₂S H 4.33, C 65.31, N 12.03 1590, 1500, 1425, 1350, 1290, 1250, br), 6.85(1H, s), 6.99(1H, d, J=7Hz, 2H, (349.414) H 4.50, C 64.91, N 11.66 1235, 1195, 1165, 1110, 830, 725 d, J=8.5Hz), 7.24(1H, d, J=7Hz3-H), 7.62(1H, d, J=8.5Hz), 7.82(1H, s) 10 3050, 2920, 2750, 2175, 1725, 1580, 3.08(2H, t, J=7Hz), 4.30(2H, t, J=7Hz), C₁₉H₁₅N₃O₂S H 4.33, C 65.31, N 12.03 1505, 1495, 1345, 1305, 1290, 1255, 6.30-8.30(1H, br), 7.12(2H, d, J=8Hz), (349.414) H 4.45, C 65.27, N 11.93 1020, 535 7.33(5H, s), 7.60(2H, d, J=8Hz), 7.82(1H, s) 11 2940, 2210, 1730, 1600, 1517, 1360, 1.34(3H, d, J=6.6Hz), 3.00-3.50(1H, C₂₀H₁₇N₃O₂S H 4.71, C 66.10, N 11.56 1268, 1180, 1019, 777, 742, 706, m), 4.17(2H, d, J=6.6Hz), 5.10(1H, (363.441) H 4.76, C 65.76, N 11.57 561, 548 br), 7.09(2H, d, J=9Hz), 7.31(5H, s), 7.58(2H, d, J=9Hz), 7.80(1H, s) 12 3050, 3020, 2930, 2775, 2220, 1720, 3.05(2H, t, J=7Hz), 4.24 C₁₉H₁₅N₃O₂S H 4.33, C 65.31, N 12.03 1620, 1600, 1490, 1350, 1290, 1220, (2H, t, J=7Hz), 6.85-7.60(9H, m), (349.414) H 4.53, C 65.64, N 11.96 1060, 1030, 990, 780, 750, 730, 700, 7.82(1H, s) 525 13 3130, 3070, 2960, 2790, 2215, 1710, 3.80-4.90(1H, br), 5.19(2H, s), C₁₈H₁₃N₃O₂S H 3.90, C 64.46, N 12.53 1600, 1590, 1510, 1365, 1260, 1240, 7.18(2H, d, J=9Hz), 7.42(5H, s), (335.387) H 4.20, C 64.52, N 12.20 1210, 1180, 985, 840, 765, 730, 595, 7.60(2H, d, J=9Hz), 7.81(1Hm s) 510 14 3050, 2930, 2750, 2195, 1715, 1595, 7.33(1H, dd, J=9Hz, 2.5Hz), 7.46- C₁₉H₁₀ClN₃O₂S H 2.65, C 60.09, N 11.06 1495, 1445, 1415, 1350, 1330, 1290, 7.83(6H, m), 8.03(2H, d, J=8Hz) (379.827) H 3.06, C 60.51, N 10.91 1260, 1240, 1165, 1060, 1035, 800, 720, 560, 540 15 3050, 2940, 2750, 2210, 1728, 1583, 3.81(3H, s), 6.87-7.90(11H, m)^(*4) C₂₀H₁₅N₃O₂S.½H₂O H 4.35, C 64.85, N 11.34 1512, 1328, 1292, 1244, 1176, 1022, (370.433) H 4.23, C 64.87, N 11.29 969, 839, 800, 707, 633, 560, 542 16 3025, 2920, 2750, 2200, 1733, 1630, 5.18(1H, br), 7.00-7.68(9H, m), C₁₇H₁₁N₃O₂S H 3.45, C 63.54, N 13.08 1600, 1485, 1340, 1286, 1260, 1220, 7.86(1H, s) (321.36)  H 3.72, C 63.61, N 12.80 754, 720, 525 17 3050, 2950, 2775, 2200, 1700, 1585, 3.60-4.70(1H, br), 5.05(2H, s), C₁₉H₁₃N₃O₄S H 3.45, C 60.15, N 11.08 1510, 1445, 1355, 1300, 1255, 1215, 5.95(2H, s), 6.80-7.05(3H, m), (379.396) H 3.74, C 59.82, N 10.96 1175, 1040, 1020, 985, 930, 830, 7.13(2H, d, J=9Hz), 7.58 810, 730, 550 (2H, d, J=9Hz), 7.68(1H, s) 18 3030, 2930, 2770, 2225, 2200, 1715, 2.31(3H, s), 4.60-6.20(1H, br), C₁₉H₁₅N₃O₂S H 4.33, C 65.31, N 12.03 1600, 1590, 1505, 1355, 1290, 1260, 5.13(2H, s), 7.00-7.47(6H, m), (349.414) H 4.52, C 65.40, N 11.78 1240, 1190, 1170, 990, 835, 800, 7.60(2H, d, J=9Hz), 7.80(1H, s) 725, 555, 540, 480 19 3050, 2930, 2780, 2225, 1720, 1620, 3.90-5.00(1H, br), 5.20(2H, s), C₁₈H₁₂ClN₃O₂S H 3.27, C 58.46, N 11.36 1610, 1595, 1510, 1360, 1290, 1260, 7.19(2H, d, J=9Hz), 7.48(4H, s), (369.832) H 3.52, C 58.65, N 11.09 1245, 1200, 1175, 1000, 850, 840, 7.63(2H, d, J=9Hz), 7.82(1H, s) 820, 720, 540, 510 20 3030, 2950, 2203, 1744, 1593, 1516, 3.92(1H, d), 4.22(1H, br), 7.09- C₂₀H₁₅N₃O₂S H 4.18, C 66.47, N 11.63 1360, 1330, 1279, 1161, 1043, 970, 7.99(10H, m), 7.85(1H, s) (361.425) H 4.35, C 66.71, N 11.35 839, 763, 698, 637, 604, 555, 520 21 3010, 2910, 2760, 2200, 1725, 1620, 3.05(2H, t, J=6.5Hz), C₁₉H₁₅N₃O₂S H 4.33, C 65.31, N 12.03 1610, 1590, 1480, 1445, 1345, 1290, 4.25(2H, t, J=6.5Hz), 6.85-7.60(9H, m), (349.414) H 4.48, C 65.34, N 12.09 1280, 1230, 1180, 1150, 750, 720, 8.01(1H, s) 690, 520 22 3500-2700, 2200, 1730, 1580, 1505, 4.00-4.80(1H, br), 7.00-7.53(7H, m), C₁₇H₁₁N₃O₂S H 3.45, C 63.53, N 13.08 1490, 1360, 1295, 1260, 1200, 1170, 7.66(2H, d, J=9Hz), 7.84(1H, s) (321.36)  H 3.79, C 63.69, N 12.93 745, 530, 480 23 3050, 2950, 2790, 2195, 1720, 1700, 3.06(2H, t, J=7Hz), 3.83(3H, s), C₂₀H₁₇N₃O₃S H 4.52, C 63.31, N 11.07 1590, 1580, 1510, 1435, 1340, 1270, 4.22(2H, t, J=7Hz), 6.95-7.50(8H, m), (379.44)  H 4.73, C 63.64, N 11.00 1250, 1220, 1170, 1145, 1020, 720, 7.77(1H, s) 545, 485 24 3050, 2950, 2770, 2190, 1735, 1650, 4.15-5.40(2H, br), 6.95- C₁₈H₁₂N₄O₂S H 3.47, C 62.06, N 16.08 1595, 1530, 1500, 1440, 1345, 1320, 7.62(3H, m), 7.62-8.30(7H, m) (348.386) H 3.71, C 62.11, N 15.92 1295, 1240, 1180, 770, 720, 690, 585, 565, 540 25 3050, 2925, 2900-2300, 2175, 1730, 7.30-8.90(m) C₁₈H₁₂N₄OS.⅓H₂O H 3.77, C 63.89, N 16.56 1640, 1610, 1510, 1470, 1425, 1320, (338.392) H 4.03, C 63.70, N 16.32 1300, 1270, 1250, 1210, 1175, 980, 820, 600, 545 26 3050, 3025, 2940, 2830, 2760, 2195, 2.97(2H, t, J=7Hz), 3.81(6H, s), C₂₁H₁₉N₃O₄S H 4.68, C 61.60, N 10.26 1730, 1700, 1600, 1500, 1450, 1420, 4.18(2H, t, J=7Hz), 6.90(2H, s), 7.10- (409.466) H 4.75, C 61.64, N 10.19 1320, 1240, 1185, 1155, 1130, 990, 7.40(5H, m), 7.80(1H, s) 730, 700, 560, 545, 530 27 3050, 2935, 2755, 2195, 1730, 1600, 3.42(3H, s), 5.50-6.40(1H, br), C₁₉H₁₄N₄O₂S.½C₂H₅OH H 4.45, C 62.32, N 14.54 1515, 1350, 1300, 1290(sh), 1245, 7.28(1H, s), 7.30(2H, d, J=8Hz), (385.448) H 4.56, C 62.19, N 14.16 1180, 1105, 720 7.54(2H, d, J=8Hz), 7.78(1H, s) 28 3060, 2940, 2800, 2230, 1720, 1635, 3.62(1H, br), 5.22(2H, s), C₁₈H₁₁BrFN₃O₂S H 2.56, C 50.01, N 9.72  1618, 1600, 1520, 1361, 1298, 1273, 7.23(2H, d, J=9Hz), 7.42-7.78(5H, m), (432.273) H 2.87, C 50.22, N 9.68  1255, 1180, 1002, 897, 852, 840, 540 7.83(1H, s) 29 3320, 3050, 2940, 2750, 2190, 1720, C₂₀H₁₂N₄O₂S.½C₃H₇NO H 3.82, C 63.15, N 15.41 1690, 1640, 1590, 1465, 1380, 1345, (408.956) H 4.12, C 62.96, N 15.40 1330, 1290, 1245, 1190, 1100, 795, 760, 725, 600, 525 30 3050, 2930, 2770, 2190, 1730, 1690, C₂₁H₁₃N₃O₂S H 3.53, C 67.91, N 11.31 1610, 1590, 1505, 1415, 1345, 1325, (371.42)  H 3.88, C 68.11, N 11.12 1290, 1265, 1240, 1195, 1180, 1090, 735, 720, 600, 540 31 3050, 3020, 2950, 2750, 2190, 1725, 7.40-8.50(m) C₂₀H₁₂N₄OS₂.⅓C₃H₇NO H 3.50, C 61.10, N 14.70 1595, 1510, 1415, 1350, 1320, 1290, (412.84)  H 3.71, C 61.02, N 14.57 1240, 1190, 1175, 760, 720, 565, 550 32 2960, 2930, 2200, 1730, 1598, 1507, 0.90(3H, t, J=7.2Hz), 1.61-2.10(2H, C₂₀H₁₇N₃O₂S H 4.71, C 66.10, N 11.56 1357, 1259, 1177, 1000, 978, 829, m), 4.40(1H, br), 5.35(1H, t, J=6.2Hz), (363.441) H 4.89, C 66.00, N 11.38 705, 523 7.05(2H, d, J=8.4Hz), 7.33(5H, s), 7.50(2H, d, J=8.4Hz), 8.73(1H, s) 33 3040, 2945, 2770, 2205, 1730, 1603, 5.19(2H, s), 5.53(1H, br), 6.94- C₁₈H₁₃N₃O₂S H 3.91, C 64.46, N 12.53 1498, 1358, 1338, 1300, 1250, 1180, 7.53(5H, m), 7.63(4H, s), 7.86(1H, s) (335.387) H 4.07, C 64.44, N 12.17 810, 753, 514 34 3045, 2950, 2750, 2200, 1737, 1595, 4.32(1H, br), 7.33-7.95(9H, m), C₁₇H₁₁N₃OS H 3.63, C 66.87, N 13.76 1490, 1339, 1179, 770, 640, 560, 547 7.91(1H, s) (305.361) C 66.93, H 3.96, N 13.70 35 3020, 2955, 2760, 2200, 1730, 1585, 1.20(6H, d, J=7Hz), 2.92(1H, septet), C₂₂H₁₉N₃OS H 5.13, C 70.75, N 11.25 1510, 1340, 1295, 1245, 1190, 1170, 3.60-4.50(1H, br), 7.15-7.90(11H, m) (373.48)  H 5.29, C 70.81, N 11.21 830, 555 36 3100, 3050, 2950, 2780, 2195, 1710, 3.50-5.00(1H, br), 4.83(2H, d, J=5 C₂₀H₁₅N₃O₂S H 4.19, C 66.50, N 11.63 1590, 1580, 1560, 1510, 1360, 1250, Hz), 6.45-6.80(2H, m), 7.18(2H, d, (361.425) H 4.40, C 66.46, N 11.41 1205, 1175, 1000, 970, 835, 730, 550 J=9Hz), 6.90-7.80(5H, m), 7.63 (2H, d, J=9Hz, 2, 6-H), 7.82(1H, s) 37 3050, 3005, 2930, 2750, 2190, 1720, 3.04(4H, t, J=6.5Hz), 4.00- C₂₇H₂₃N₃O₃S H 4.94, C 69.06, N 8.95  1590, 1500, 1460, 1345, 1300, 1270, 4.45(4H, m), 6.90-7.60(13H, m), (469.565) H 5.09, C 69.02, N 8.64  1250, 1210, 1165, 1135, 1010, 745, 7.78(1H, s) 715, 690 38 3050, 2930, 2770, 2200, 1720(sh), 3.09(2H, t, J=7Hz), 4.27(2H, t, J=7Hz), C₁₉H₁₅N₃O₃S H 4.14, C 62.45, N 11.50 1710, 1595, 1505, 1455, 1360, 1280, 6.90-7.55(8H, m), 7.71(1H, s) (365.413) H 4.30, C 62.16, N 11.13 1250, 1210, 1170, 1135, 1010, 720, 700, 510 39 3060, 2950, 2930, 2770, 2195, 1720, 7.40-8.20(m) C₁₈H₁₂N₄O₂S H 3.47, C 62.06, N 16.08 1705, 1655, 1590, 1510, 1485, 1415, (348.386) H 3.74, C 62.12, N 15.86 1350, 1320, 1295, 1240, 1185, 710, 630, 610, 535 40 3050, 2950, 2760, 2200, 1715, 1595, 3.50-4.35(1H, br), 6.95-8.15(14H, m) C₂₅H₁₅N₃OS.C₂H₅OH H 4.69, C 71.82, N 9.31  1445, 1350, 1290, 1240, 1190, 1170, (451.55)  H 4.80, C 72.12, N 9.18  775, 730, 610, 540 41 3120, 3060, 2945, 2780, 2190, 1710, 4.37(4H, br), 6.80-7.47(7H, m), 7.47- C₁₉H₁₅N₃O₃S H 4.14, C 62.45, N 11.50 1600, 1505, 1485, 1450, 1360, 1260, 7.75(3H, m)^(*4) (365.413) H 4.32, C 62.39, N 11.44 1250, 1230, 1200, 1170, 1065, 955, 830, 760, 725, 540 42 3045, 2975, 2210, 1710, 1600, 1512, 3.93(3H, s), 5.25(1H, br), 7.11- C₂₀H₁₅N₃O₂S H 4.18, C 66.47, N 11.63 1365, 1282, 1252, 1219, 1199, 1036, 7.92(10H, m), 7.93(1H, s) (361.425) H 4.44, C 66.43, N 11.27 970, 823, 730, 540 43 3050, 2940, 2760, 2195, 1705, 1570, 3.10(2H, t, J=7Hz), 4.27(2H, t, J=7Hz), C₁₉H₁₅N₃O₃S H 4.14, C 62.45, N 11.50 1510, 1350, 1300, 1285, 1220, 1190, 6.90-7.60(8H, m), 7.79(1H, s) (365.413) H 4.28, C 62.26, N 11.33 1125, 720, 695 44 3050, 2955, 2760, 2200, 1733, 1597, 1.01(3H, t, J=7Hz), 2.52(2H, m), C₂₁H₁₇N₃OS H 4.77, C 70.17, N 11.69 1350, 1297, 1223, 1190, 700 4.19(1H, br), 6.54(1H, s), 6.92- (359.453) H 4.96, C 70.15, N 11.52 7.69(9H, m), 7.73(1H, s) 45 3130, 3060, 2980, 2200, 1703, 1604, 5.43(1H, br), 7.38-7.93(9H, m), C₁₇H₁₁N₃OS H 3.63, C 66.87, N 13.76 1594, 1353, 1240, 760, 720, 700, 542 7.96(1H, s) (305.361) H 3.99, C 66.96, N 13.49 46 3080, 2955, 2205, 1735, 1597, 1502, 3.87(3H, s), 4.56(2H, s), 4.62(2H, s), C₂₀H₁₇N₃O₃S H 4.52, C 63.31, N 11.07 1363, 1274, 1205, 1140, 1110, 1037, 7.04-7.71(8H, m), 7.80(1H, s), (379.44)  H 4.64, C 63.20, N 10.79 742, 560, 493 47 3050, 2200, 1736, 1600, 1500, 1343, 4.55(1H, br), 6.89-7.60(15H, m), C₂₅H₁₇N₃OS H 4.20, C 73.69, N 10.31 1330, 1297, 1188, 772, 707, 640, 7.77(1H, s) (407.497) H 4.47, C 73.83, N 10.00 616, 550 48 3050, 2950, 2760, 2195, 1770, 1710, 3.90-4.50(4H, m), C₂₁H₁₄N₄O₄S H 3.37, C 60.28, N 13.39 1590, 1510, 1390, 1350, 1250, 1170, 7.04(2H, d, J=8.5Hz), (418.433) H 3.62, C 60.27, N 13.10 1120, 720 7.53(2H, d, J=8.5Hz), 7.60(1H, s), 7.88(4H, s)^(*4) 49 3060, 2930, 2750, 2190, 1730, 1640, 4.71(2H, s), 7.18-7.80(8H, m), 7.80- C₁₉H₁₂N₄OS₃ H 3.67, C 55.16, N 14.30 1600, 1455, 1430, 1350, 1295, 1245, 8.10(2H, m)^(*4) ⅔C₃H₇NO H 3.75, C 55.46, N 14.00 1195, 1180, 1000, 760, 715, 545 (459.26)  50 3040, 2930, 2760, 2220, 1736, 1617, 3.92(1H, br), 7.20-7.87(10H, m), C₁₉H₁₂ClN₃OS H 3.31, C 62.38, N 11.49 1590, 1357, 1298, 1181, 1094, 838, 7.83(1H, s) (365.844) H 3.53, C 62.48, N 11.46 734, 538 51 3070, 2950, 2200, 1722, 1600, 1515, 2.67(3H, s), 3.06(2H, t, J=6Hz), C₂₀H₁₇N₃O₂S.¼H₂O H 4.79, C 65.29, N 11.42 1342, 1250, 1178, 1020, 836, 754, 3.86(1H, br), 4.28(2H, t, J=6Hz), (367.945) H 4.86, C 65.47, N 11.02 700, 540 7.06(2H, d, J=9Hz), 7.30(5H, s), 7.46(2H, d, J=9Hz) 52 3050, 2940, 2770, 2220, 1740, 1620, 4.40(1H, br), 7.45(2H, s), 7.50- C₂₀H₁₂F₃N₃OS H 3.03, C 60.15, N 10.52 1600, 1323, 1300, 1180, 1121, 1070, 7.90(8H, m), 7.83(1H, s) (399.393) H 3.25, C 60.28, N 10.63 838, 727, 526 53 3030, 2920, 2770, 2210, 2200, 1720, 5.18(2H, s), 5.70(1H, br), 7.02- C₁₈H₁₃N₃O₂S H 3.91, C 64.46, N 12.53 1630, 1612, 1491, 1424, 1357, 1300, 7.65(9H, m), 7.80(1H, s) (335.387) H 4.09, C 64.35, N 12.37 1226, 1023, 786, 740, 723, 525 54 3060, 2960, 2790, 2200, 1700, 1592, 3.60(1H, br), 4.32(2H, s), 7.15- C₁₈H₁₃N₃OS₂ H 3.73, C 61.52, N 11.96 1577, 1541, 1494, 1408, 1358, 1300, 7.58(9H, m), 7.77(1H, s) (351.454) H 3.97, C 61.53, N 12.04 1254, 1192, 1089, 832, 814, 723, 589, 570, 554, 525, 437 55 3090, 2200, 1720, 1589, 1519, 1352, 2.32(3H, s), 5.13(1H, s), 7.10- C₂₀H₁₅N₃OS H 4.38, C 69.54, N 12.16 1300, 1178, 978, 826, 730, 550 7.73(11H, m)^(*4) (345.426) H 4.66, C 70.12, N 11.48 56 3060, 2950, 2760, 2180, 1727, 1587, 3.08(2H, t, J=6.8Hz), C₁₉H₁₄ClN₃O₂S H 3.68, C 59.45, N 10.95 1510, 1262, 1179, 1018, 826, 797, 4.30(2H, t, J=6.8Hz), 4.30(1H, br), (383.859) H 3.87, C 59.67, N 10.65 723, 540 7.13(2H, d, J=9Hz), 7.38(4H, s), 7.62(2H, d, J=9Hz), 7.83(1H, s) 57 3175, 3100, 3080, 3040, 2950, 2770, 3.80-5.80(1H, br), 5.26(2H, s), 7.10- C₁₈H₁₂ClN₃O₂S H 3.27, C 58.46, N 11.36 2200, 1740, 1593, 1585, 1487, 1460, 7.70(8H, m), 7.91(1H, s) (369.832) H 3.49, C 58.35, N 10.98 1350, 1294, 1252, 1220, 1179, 1027, 935, 750, 742, 721, 550 58 3110, 3060, 3030, 2960, 2775, 2200, 2.92(4H, s), 7.00-7.70(9H, m), C₁₉H₁₅N₃OS H 4.53, C 68.45, N 12.60 1505, 1600, 1588, 1352, 1299, 1251, 7.82(1H, s) (333.415) H 4.72, C 68.70, N 12.37 1198, 1175, 760, 728, 700 59 3120, 3078, 3055, 3024, 2966, 2790, 5.30-6.40(1H, br), 7.10-8.00(12H, m) C₁₉H₁₃N₃OS H 3.95, C 68.86, N 12.68 2200, 1729, 1705, 1609, 1590, 1355, (331.399) H 4.24, C 68.90, N 12.27 1314, 1294, 1265, 1245, 1225, 1200, 1165, 960, 788, 755, 720, 689, 528 60 3060, 3040, 2950, 2775, 2195, 1730, 2.22, 2.39(each 3H, s), 5.19(2H, s), C₂₀H₁₇N₃O₂S H 4.71, C 66.10, N 11.56 1685, 1590, 1505, 1310, 1270, 1230, 7.07(1H, s), 7.19(1H, s), 7.23- (363.441) H 4.97, C 66.34, N 11.34 1095, 995, 730 7.65(5H, m), 7.86(1H, s) 61 3060, 3020, 2930, 2827, 2765, 2189, 2.71(3H, s), 3.78(3H, s), 6.75- C₂₁H₁₇N₃O₂S.⅓H₂O H 4.67, C 66.12, N 11.02 1716, 1592, 1519, 1334, 1250, 1216, 7.85(10H, m) (381.457) H 4.92, C 66.22, N 10.80 1173, 1027, 968, 833, 563, 539

EXAMPLE 62

2-(N-Cyanoimino)-5-[(E)-4-stylylbenzylidene]thiazolidin-4-one Potassium Salt: Potassium Salt of the Compound of Example 1

The crude product (18.98 g) was recrystallized from 65% isopropanol to yield the title compound as yellow powder (10.87 g).

mp: >300° C. IR (KBr, cm⁻¹): 3025, 2180, 1750, 1590, 1490, 1420, 1340, 1290, 1205, 1180, 960, 820, 745, 540; ¹H-NMR (DMSO-d6, ppm): δ 7.25-7.55 (6H, m), 7.55-7.85 (6H, m).

PHARMACOLOGICAL EXAMPLES EXAMPLE 63

Hypotriglyceridemic Activity in Fructose-induced Hyperlipidemic Rats

The compounds were tested for a hypotriglyceridemic activity in fructose-induced hyperlipidemic rats in accordance with the method described in Nippon Yakurigaku Zasshi, 92 (3), 175-180 (1988). Sprague Dawley rats were divided into experimental groups with a comparable mean body weight. 75% fructose solution as drinking water was given to the animals for 7 days, while normal water was given to the intact groups ad libitum. During the experimental period the test compounds suspended in 3% gum arabic were given to the test group orally once a day in a daily dose of 30 mg/kg. The vehicle solution was given to the control group and the intact group. After 2 hours from the final administration, blood was collected from the abdominal aorta under ether anesthesia, and levels of total cholesterol and triglyceride in the serum were measured. The results are shown in Table 2. The reduction rate (%) was calculated according to the following equation: ${{Reduction}\quad {rate}\quad (\%)} = {{{}\left\lbrack {1 - \frac{\left( {{measured}\quad {triglyceride}\quad {level}\quad {in}\quad {each}\quad {treated}\quad {group}} \right)}{\left( {{measured}\quad {triglyceride}\quad {level}\quad {in}\quad {control}\quad {group}} \right)}} \right\rbrack} \times 100}$

Above experimental model is well known as a model of hypertriglicemia. As shown in Table 2, the compounds of the present invention have a serum trigriceride reducing activity.

TABLE 2 The hypotriglyceridemic activity in fructose induced hyperlipidemic rats Triglyceride Triglyceride Compound (% Reduction) Compound (% Reduction) Example 1 47 Example 20 54 Example 2 67 Example 21 48 Example 3 64 Example 22 65 Example 4 42 Example 26 46 Example 6 84 Example 28 36 Example 7 60 Example 32 47 Example 8 47 Example 34 71 Example 9 49 Example 37 41 Example 10 39 Example 39 57 Example 11 62 Example 40 42 Example 12 59 Example 43 67 Example 13 55 Example 45 43 Example 14 36 Example 47 69 Example 15 47 Example 49 39 Example 16 54 Example 51 67 Example 17 37 Example 52 44 Example 19 38 At a dose of 30 mg/kg p.o.

EXAMPLE 64

Lipid Lowering Effects in High Cholesterol-fed Hamsters

The compounds were tested for lipid lowering effects in high cholesterol-fed hamsters in accordance with the method described in Jpn Pharmacol Ther, 23 (suppl 4), s1047-1053 (1995). Male Syrian hamsters were fed the high cholesterol diet supplemented with 1% cholesterol and 10% coconut oil for 3 weeks. Before drug administration, blood was collected from the orbital venous plexus under ether anesthesia, and a serum total cholesterol level was measured. The animals were divided into groups so as to have a comparable mean total cholesterol level. The designated doses of the compound of Example 1 or Bezafibrate were administrated to test groups and the vehicle solution was given to the control group orally once a day for 7 days under the high cholesterol diet feeding. The intact group of animals were fed normal diet. After 4 hours of the final administration, blood was collected by cardiac puncture, and the total cholesterol and triglyceride levels in the serum were determined by the enzymatic method.

The results are shown in Table 3. The reduction rate (%) was calculated according to the following equation: ${{Reduction}\quad {rate}\quad (\%)} = {{{}\left\lbrack {1 - \frac{\left( {{measured}\quad {lipid}\quad {level}\quad {in}\quad {each}\quad {treated}\quad {group}} \right)}{\left( {{measured}\quad {lipid}\quad {level}\quad {in}\quad {control}\quad {group}} \right)}} \right\rbrack} \times 100}$

The result indicates that the compound of Example 1 has potent reducing activities in serum cholesterol and triglyceride levels and it is more effective than bezafibrate.

TABLE 3 Effect of the compound of Example 1 and bezafibrate on serum lipid levels in high cholesterol-fed hamsters Bezafibrate Compound of Example 1 Total Total Compound cholesterol Triglyceride cholesterol Triglyceride Activity (% Reduc- (% Reduc- (% Reduc- (% Reduc- Dose tion)* tion)* tion) (tion) 15 mg/kg — — 26 60 30 mg/kg −5 −21 25 62 60 mg/kg −0 −18 29 69 120 mg/kg 20 16 41 80 *A minus quantity represents the rate of increase.

EXAMPLE 65

Lipid Lowering Effects in High Cholesterol-fed Hamsters

The compounds of the present invention were evaluated for selecting more effective lipid lowering activities in the same manner described in Example 64 at a dose of 15 mg/kg p.o. The results are shown in Table 4. The reduction rate (%) was calculated according to the following equation: ${{Reduction}\quad {rate}\quad (\%)} = {{{}\left\lbrack {1 - \frac{\left( {{measured}\quad {lipid}\quad {level}\quad {in}\quad {each}\quad {treated}\quad {group}} \right)}{\left( {{measured}\quad {lipid}\quad {level}\quad {in}\quad {control}\quad {group}} \right)}} \right\rbrack} \times 100}$

TABLE 4 Hypolipidemic effects in high cholesterol-fed hamsters Total cholesterol Triglyceride Compound (% Reduction) (% Reduction) Example 2 27 57 Example 3 16 17 Example 7 18 12 Example 9 15 15 Example 14 11 24 Example 15 32 61 At a dose of 15 mg/kg p.o.

EXAMPLE 66

Acute Toxicity

The single dose toxicity of the compound of Example 1 and Example 10 were evaluated after oral administration at a dose of 2000 mg/kg with each group comprising 3 mice. The animals were observed daily for 2 weeks after the administration. As a result, no deaths were observed.

EXAMPLE 67

Mutagenicity Test

The mutagenicity of the compound of Example 1 was examined by a reverse mutation test using Salmonella typhimurium TA100 and TA98 in the absence or presence of S9 mix. The compound of Example 1 did not increase the number of revertant colonies, and was not mutagenic in this test system. 

What is claimed is:
 1. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I or a pharmaceutically acceptable salt or solvate thereof:

wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C₁-C₄ alkyl group, a haloalkyl group, a halogen atom and —OR⁵; R¹ represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C₁-C₄ alkylene or alkenylene group optionally substituted by a phenyl group, R⁶—X, X—R⁶, X—R⁶—X, R⁶—X—R⁶, —C(═O)—NR⁷— or —NR⁷—C(═O)—; R² and R³ are the same or different and each represents a hydrogen atom, a C₁-C₄ alkyl group, —OR⁸ or a halogen atom; R⁴ represents a hydrogen atom or a C₁-C₄ alkyl group; R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group; R⁶ represents a straight or branched C₁-C₄ alkylene or alkenytene group; R⁷ represents a hydrogen atom or a C₁-C₄ alkyl group; R⁸ represents a hydrogen atom, a C₁-C₄ alkyl group or an aralkyl group; X represents an oxygen atom or a sulfur atom.
 2. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein ring A represents a benzene ring, a benzodioxole ring, a benzofuran ring, a benzothiazole, a fluorene ring, an indan ring, an indoline ring or a pyridine ring, each of which may be substituted by one or more substituents selected from a straight or branched C₁-C₄ alkyl group, a haloalkyl group, a halogen atom and —OR⁵; R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group.
 3. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein ring A represents a benzene ring which may be substituted by one or more substituents selected from a straight or branched C₁-C₄ alkyl group, a haloalkyl group, a halogen atom and —OR⁵; R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group.
 4. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R¹ represents a methyne group or a straight or branched C₁-C₄ alkylene or alkenylene group optionally substituted by a phenyl group.
 5. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R¹ represents an oxygen atom or a sulfur atom.
 6. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R¹ represents a single bond.
 7. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R¹ represents R⁶—X, X—R⁶, X—R⁶—X or R⁶—X—R⁶; R⁶ represents a straight or branched C₁-C₄ alkylene or alkenylene group; X represents an oxygen atom or a sulfur atom.
 8. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R¹ represents —C(═O)—NR⁷— or —NR⁷—C(═O)—; R⁷ represents a hydrogen atom or a C₁-C₄ alkyl group.
 9. Novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the compound of formula I is any one of the following: 2-(N-Cyanoimino)-5-[(E)-4-stylylbenzyidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[(E)-4-(a-methylstylyl)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(benzyloxymethyl)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[(E)-4-(b-methylstylyl)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(3-phenylpropoxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(4-chlorophenoxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(4-phenylthiobenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-[(E)-4-(2-fluorostylyl)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(2-dimethylphenoxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(4-phenethyloxybenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(2-phenylpropoxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(3-phenethyloxybenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-(4-benzyloxybenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(5-chlorobenzofuran-2-yl)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[(E)-4-(4-methoxystylyl)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(3-phenoxybenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(1,3-benzodioxol-5-ylmethoxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(4-methylbenzyloxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(4-chlorobenzyloxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[3-methoxy-(E)-4-stylylbenzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(2-phenethyloxybenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-(4-phenoxybenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-[3-(benzyloxy)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-(benzylthio)benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(4-phenethylbenzylidene)thiazolidin-4-one; 2-(N-Cyanoimino)-5-[4-[2-(4-chlorophenyl)ethoxy]benzylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-[1-[(E)-4-(4-methoxystylyl)phenyl]ethylidene]thiazolidin-4-one; 2-(N-Cyanoimino)-5-(4-benzyloxy-2,5-dimethylbenzylidene)thiazolidin-4-one; or 2-(N-Cyanoimino)-5-[(E)-3-stylylbenzylidene]thiazolidin-4-one.
 10. A process for preparing a 2-(N-cyanoimino)thiazolidin-4-one derivatives or a pharmaceutically acceptable salt or solvate thereof according to claim 1, which comprises reacting a compound represented by formula II, or salts thereof, with an aldehyde or ketone represented by formula III:

wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C₁-C₄ alkyl group, a haloalkyl group, a halogen atom and —OR⁵; R¹ represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C₁-C₄ alkylene or alkenylene group optionally substituted by a phenyl group, R⁶—X, X—R⁶, X—R⁶—X, R⁶—X—R⁶, —C(═O)—NR⁷— or —NR⁷—C(═O)—; R² and R³ are the same or different and each represents a hydrogen atom, a C₁-C₄ alkyl group, —OR⁸ or a halogen atom; R⁴ represents a hydrogen atom or a C₁-C₄ alkyl group; R⁵ represents a hydrogen atom or a C₁-C₄ alkyl group; R⁶ represents a straight or branched C₁-C₄ alkylene or alkenylene group; R⁷ represents a hydrogen atom or a C₁-C₄ alkyl group; R⁸ represents a hydrogen atom, a C₁-C₄ alkyl group or an aralkyl group; X represents an oxygen atom or a sulfur atom.
 11. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
 12. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 as an active ingredient and a pharmaceutically acceptable carrier.
 13. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 3 as an active ingredient and a pharmaceutically acceptable carrier.
 14. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 4 as an active ingredient and a pharmaceutically acceptable carrier.
 15. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 5 as an active ingredient and a pharmaceutically acceptable carrier.
 16. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 6 as an active ingredient and a pharmaceutically acceptable carrier.
 17. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 7 as an active ingredient and a pharmaceutically acceptable carrier.
 18. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 8 as an active ingredient and a pharmaceutically acceptable carrier.
 19. A pharmaceutical composition for treating hyperlipidemia comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives and/or a pharmaceutically acceptable salt and/or solvate thereof according to claim 9 as an active ingredient and a pharmaceutically acceptable carrier. 